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Old 05-24-2009, 09:26 PM   #1
Rich66
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Zoledronate and variants: A New Weapon Against Tumor Cells

(Simultaneous Hif/VEGF, IGF, CSC, PI3k/Akt, chemo replacer for adjuvant?, monotherapy non-skeletal cases, weekly for BC and antiangiogenic effect, against persistent isolated cells, timing to potentiate chemo, timing w/endocrine,w/doxycycline,w/cisplatinum,w/fluvastatin, w/gossypol, w/rads, prevention, side effects, dosing, BM-EPC marker controversy, side effects thread, oral ibandronate, increased neoadj PCR, reverses GM-CSF induced growth)




Curr Cancer Drug Targets. 2010 Jan 1. [Epub ahead of print]
Can we Consider Zoledronic Acid a New Antitumor Agent? Recent Evidence in Clinical Setting.

Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, Calipari N, Ottaviani D, Ibrahim T.
Medical Oncology, University Campus Bio-Medico, Rome, Italy d.santini@unicampus.it.
New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

PMID: 20088792 [PubMed - as supplied by publisher]



1: Curr Med Chem. 2007;14(20):2126-35. Links
Zoledronic acid - a multiplicity of anti-cancer action.

Yuasa T, Kimura S, Ashihara E, Habuchi T, Maekawa T.
Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan. yuasa@doc.med.akita-u.ac.jp
Bisphosphonates (BPs) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BPs, zoledronic acid (ZOL) has the strongest activity of anti-bone resorption and shows diverse direct anti-cancer effects in vitro. Some chemical and biological characteristics of ZOL indicate the potential for in vivo growth inhibition and the mechanisms responsible for the observed anti-cancer effects are beginning to be elucidated. ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Consequently, it inhibits the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells. ZOL, which has a high affinity for mineralized bone, rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL also blocks osteolysis and osteoclastgenesis, thus preventing the release of various growth factors which are abundantly stored in bone. Moreover, ZOL stimulates gammadelta T cells, which play important roles in innate immunity against cancer. In addition, ZOL is also a potent inhibitor of angiogenesis, probably due to the modification of various angiogenic properties of endothelial cells. Furthermore, ZOL synergizes with a variety of anticancer agents including chemotherapeutic drugs, molecular targeted agents, and other biological agents. Based on these potential anti-cancer properties, several clinical trials have been initiated to test the combination of ZOL and other agents. The accumulated encouraging evidence to date indicate that ZOL is an attractive anti-cancer agent which promises to be the next exciting therapy for patients with various cancers.


Jpn J Clin Oncol. 2009 Nov;39(11):745-50. Epub 2009 Oct 6.
A case of bone, lung, pleural and liver metastases from renal cell carcinoma which responded remarkably well to zoledronic acid monotherapy.

Miwa S, Mizokami A, Konaka H, Izumi K, Nohara T, Namiki M.
Department of Integrative Cancer Therapy and Urology, 13-1 Takara-machi, Kanazawa City 920-8640, Japan.
Herein, we report a rare case in which bisphosphonate zoledronic acid (ZA) effectively treated not only multiple bone metastases but also lung, pleural and liver metastases from renal cell carcinoma (RCC). Recently, ZA is used to treat skeletal-related events (SREs) such as bone pain caused by bone metastasis from many kinds of cancer. The patient in the present report had multiple bone metastases from RCC. Remarkable improvement of the bone metastasis was observed following treatment with ZA at a dosage of 4 mg administered once every 4 weeks. Moreover, lung, pleural and liver metastases also diminished markedly in size in response to the treatment. The metastases have shown no progression for 20 months since starting the ZA treatment. We believe that the present report is the first of its kind announcing that ZA monotherapy has been effective for lung, pleural and liver metastases from RCC.

PMID: 19808839 [PubMed - indexed for MEDLINE]





Curr Cancer Drug Targets. 2009 Nov;9(7):791-800.
Cutting the limits of aminobisphosphonates: new strategies for the potentiation of their anti-tumour effects.

Marra M, Abbruzzese A, Addeo R, Del Prete S, Tassone P, Tonini G, Tagliaferri P, Santini D, Caraglia M.
Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli no16, 80138 Naples, Itlay.
Therapy with aminobisphosphonate (N-BPs), and zoledronic acid (ZOL) especially, has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that N-BPs exert their direct or indirect anti-tumour effects on cancer growth factor release, cancer cell adhesion, invasion and viability, cancer angiogenesis and cancer cell apoptosis. Here, we will discuss the molecular mechanisms of the antitumour effects induced by ZOL. Despite their well-established in vitro anti-tumour effects N-BPs have not clear in vivo anti-tumour activity in humans. The bases of these discrepancies will be discussed in the text with a special focus on the pharmacokinetic limits of N-BPs. Moreover, the following molecular and pharmacological strategies in order to overcome N-BPs limitations will be described: i) development of pharmacological combinations with other biological agents; ii) finding of new molecular targets of N-BPs; iii) development of new pharmacological formulations of N-BPs. Finally, a new scenario of integrated bio-medicine and pharmacology will be depicted in order to drive the optimization of anti-cancer activity of N-BPs.

PMID: 20025567 [PubMed - in process]





Bone. 2009 Dec;45(6):1153-60. Epub 2009 Aug 21.
The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro.

Mitrofan LM, Pelkonen J, Mönkkönen J.
Faculty of Pharmacy, Department of Pharmaceutics, University of Kuopio, Finland.
Bisphosphonates are potent inhibitors of osteoclast function widely used to treat excessive bone resorption associated, e.g., with bone metastases. They have also antitumor activity. However, it is unclear whether this reflects an indirect effect via inhibition of bone resorption or a direct antitumor effect. Nitrogen-containing bisphosphonates (N-BPs), including zoledronic acid (ZOL), act by inhibiting farnesyl pyrophosphate synthase (FPPS). The mevalonate pathway is blocked and the accumulation of isopentenyl pyrophosphate (IPP) consequently occurs. IPP is conjugated to AMP to form a novel ATP analog (ApppI). The present study was undertaken to clarify whether IPP and/or ApppI has a direct involvement in apoptosis caused by ZOL in different cancer cell lines. There are marked differences in ZOL-induced ApppI formation between different cancer cell lines. On this basis, we selected three cancer cell lines that differ significantly from each other in their ZOL-induced IPP and ApppI accumulation: human estrogen-dependent (MCF7) and estrogen-independent (MDA-MB 436) breast cancer cell lines and a human myeloma cell line (RPMI 8226). The amount of IPP/ApppI correlated with the capacity of cells to undergo apoptosis. Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, blocks both IPP and ApppI formation and to some degree ZOL-induced apoptosis in a cell line-dependent manner. In addition, lovastatin (LOV), an inhibitor of the enzyme HMGCoA reductase, completely blocks IPP/ApppI formation as determined by mass spectrometry analysis, but enhances apoptosis. In conclusion, the current data suggest that ZOL-induced IPP/ApppI formation can contribute to ZOL-induced apoptosis. This mechanism and the inhibition of protein prenylation, both outcomes of FPPS inhibition in mevalonate pathway, seem to act in concert in ZOL-induced apoptosis in cancer cells.

PMID: 19699819 [PubMed - in process]





Zoledronic Acid and Angiogenesis


http://clincancerres.aacrjournals.or...s;13/22/6850-a

There is growing scientific evidence that better targeting of the bisphosphonates to cells outside bone could more likely be achieved by more frequent administration of low doses (2, 3). These data are supported by the pharmacokinetic profile of zoledronic acid (ZA). This bisphosphonate is prevalently accumulated into the bone and constantly dismissed in the circulation at very low concentrations by the bone turnover. As a consequence, its circulating plasma levels are low and short lasting. For this reason, repeated pulses of ZA could be useful in the maintenance of active plasma concentrations of ZA. Thus, metronomic (commonly identified as intermittent administration of low doses of anticancer drugs) bisphosphonate administration may lead to significant intracellular accumulation over time in tumor cells. Although the precise mechanism of this effect is still not well known, it is reasonable to hypothesize that clinical fractionated dosing of ZA may inhibit several antiangiogenic-related cascades at different cellular and molecular levels. It has been shown that ZA may affect angiogenesis (i.e., the formation of new vessels by sprouting of preexisting mature endothelial cells and inhibiting endothelial cell adhesion and migration) but only at higher concentrations (4). On the other hand, we may hypothesize that, at lower concentrations, such as during metronomic administration, ZA could affect vasculogenesis (i.e., the creation of primordial vessels from endothelial progenitor cells derived from bone marrow; ref. 5). The endothelial progenitor cells possess the ability to migrate, colonize, proliferate, and, ultimately, differentiate into endothelial lineage cells appearing to contribute to tumor vessel formation by incorporating into the neoendothelium. (6). The inhibition of endothelial progenitor cell mobilization results in retardation of tumor growth (6). Vascular endothelial growth factor (VEGF) induces the proliferation, differentiation, and chemotaxis of endothelial progenitor cells and is essential for survival of these progenitors (7). It has been shown that circulating endothelial cell levels can be altered by chemotherapeutic and antiangiogenic treatments, such as metronomic chemotherapy or VEGF inhibitors (8). For all these reasons, we could hypothesize that fractioned and intermittent administration of ZA may target directly EPCs. Therefore, based on this stimulating hypothesis, we intend to investigate the effects in humans of ZA therapy on the number and functions of circulating EPCs.




Effect of metronomic use of zoledronic acid (ZOL) on antitumor and antiosteoclastic effects in breast cancer patients with bone metastasis.


Sub-category: Antiangiogenic or Antimetastatic Agents
Category: Developmental Therapeutics: Molecular Therapeutics
Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27, 2009 (suppl; abstr e14603)
Abstract No: e14603

Author(s): H. Xi-Chun, X. Zhao, X. Xu, H. Guo, Z. Wang, X. Guo, J. Chen, J. Wu, Z. Shao, J. Li, B. Zhu; Cancer Hospital of Fudan University, Shanghai, China

Abstract:
Background: Zoledronic acid (ZOL) can reduce the risk of skeletal-related events (SREs) and may have direct and indirect antitumor effects, which have been shown in animal models, pilot clinical studies as well as in recent phase III randomized trials. However, the pharmacokinetics of the drug in breast cancer patients remains to be elucidated and optimized. The purpose of this randomized study was to compare the effects of ZOL on osteoclasts and angiogenesis between a weekly low-dose versus a conventional dosage. Methods: Sixty breast cancer patients with bone metastases were recruited in this randomized phase II clinical study. The participants either received ZOL 1mg IV weekly for 4 doses or a single dose of ZOL 4mg IV. No other antitumor treatments were administered. During the first month after initial infusion of ZOL, serial blood samples were collected on day 1, 15 and 29 measuring markers for bone resorption (NTx), angiogenesis (VEGF), and tumor burden (CEA and CA15-3). Results:Compared to a single-dose administration, weekly low dose of ZOL resulted in a greater reduction in serum levels of VEGF and NTx, with a significant trend over time during one month observation. There were no statistically significant differences in circulating levels of CEA and CA15-3 between the two dosing regimens. Patients who received metronomic ZOL had a longer median time to disease progression (TTP) (7.0 months, 95%CI, 6.1-7.9 months) than those who had a single dose of ZOL (2.8 months, 95%CI, 0-5.7 months; p=0.076). Conclusions: The metronomic use of low-dose ZOL 1 mg appeared to be more effective than the conventional regimen in the long-lasting reduction of VEGF and NTx, and in prolonging TTP. This dosing schedule should be further assessed in phase III trials as we demonstrated that ZOL 1mg has greater antitumor properties in our study.
Cancer Therapy: Clinical




Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients

Daniele Santini1, Bruno Vincenzi1, Sara Galluzzo1, Fabrizio Battistoni2, Laura Rocci1, Olga Venditti1, Gaia Schiavon1, Silvia Angeletti2, Federica Uzzalli1, Michele Caraglia3, Giordano Dicuonzo2 and Giuseppe Tonini1 Authors' Affiliations: 1 Medical Oncology and 2 Department of Laboratory Medicine, University Campus Bio-Medico, Rome, Italy, and 3 Experimental Pharmacology Unit, National Cancer Institute of Naples "Fondazione G. Pascale," Naples, Italy
Requests for reprints: Daniele Santini, Medical Oncology, University Campus Bio-Medico, 00155 Rome, Italy. Phone: 39-6-2254-1737; Fax: 39-6-2254-1520; E-mail: d.santini@uicampus.it.
Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies.
Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion.
Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion.
Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.


Cancer Biol Ther. 2010 Sep 8;10(6). [Epub ahead of print]
Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: Phase I ZANTE trial.

Facchini G, Caraglia M, Morabito A, Marra M, Piccirillo MC, Bochicchio AM, Striano S, Marra L, Nasti G, Ferrari E, Leopardo D, Vitale G, Gentilini D, Tortoriello A, Catalano A, Budillon A, Perrone F, Iaffaioli RV.
Genito-Urinary Department, National Cancer Institute "Fondazione G. Pascale", Naples, Italy.


purchase TEXT

Abstract

Background: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid ANd TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. Results: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. Patients and Methods: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. Conclusions: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.

PMID: 20657175 [PubMed - as supplied by publisher]



Metronomic weekly use of zoledronic acid for breast cancer with
bone metastases




1: J Surg Res. 2009 Jan;151(1):115-20. Epub 2008 Feb 29. Links
Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation.

Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Shuno Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H.
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan. jymda-tky@umin.ac.jp
BACKGROUND: Zoledronic acid (ZOL) is clinically available for the treatment of skeletal complications. In preclinical studies, strong anti-cancer activities against breast cancer, prostate cancer, and leukemia were reported. It also inhibited the proliferation of cultured human endothelial cells, suggestive of an anti-angiogenic activity. Since ZOL has the tendency to accumulate in bone, we investigated the effect of ZOL on endothelial progenitor cells (EPCs), which originate from the bone marrow, and play important roles in angiogenesis. MATERIALS AND METHODS: Human peripheral blood mononuclear cells were cultured for 7 d to differentiate into EPCs. Cells were treated without/with ZOL or with geranylgeraniol (GGOH). Their endothelial phenotype was confirmed by the expression of CD144 and vascular endothelial growth factor receptor 2 and the tube-like formation ability on Matrigel (Becton Dickinson, Bedford, MA). Annexin V/propidium iodide staining was used to analyze apoptosis. RESULTS: ZOL treatment, even at low doses, from d 2 to 7 of culture resulted in impaired EPC differentiation and could be restored by co-treatment with GGOH. On the other hand, treatment of putative EPCs with ZOL at concentrations higher than 10 mum resulted in induction of apoptosis.
CONCLUSION: ZOL dose-dependently inhibited the differentiation of EPCs, the effect being observed even at low drug levels. At high concentrations, ZOL also induced the apoptotic death of putative EPCs. Since GGOH restored the inhibitory effect of ZOL on EPCs differentiation, the effect of ZOL appears to be dependent on the inhibition of prenylation of small-G-proteins. From these findings, we conclude that ZOL could be a potential anticancer agent by inhibiting angiogenesis.

1: J Immunol. 2009 Jun 1;182(11):7287-96. Links

Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.

Todaro M, D'Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G.
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vgamma9Vdelta2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-alpha and IFN-gamma) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vgamma9Vdelta2 T cells to sensitized targets. Vgamma9Vdelta2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.



Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods
  • It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.
Results
  • Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
  • Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
  • The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
  • The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.

The breast cancer revolution that saves women from chemo

By Jerome Burne
Last updated at 11:10 PM on 16th November 2009

A diagnosis of breast cancer usually means having chemotherapy to stop the cancer coming back. But if you're a patient in Austria, you're unlikely to be given chemo as a treatment.
And yet you'll do better than patients who undergo the treatment, as well as avoiding the gruelling side effects, says a leading Austrian cancer specialist in an article to be published in the medical magazine, The Lancet, later this month.
'There has been too much emphasis on adding chemotherapy to breast cancer treatment,' the article's author, Professor Michael Gnant, told the Mail. 'It's toxic, with often too little gain. In Austria, we've been treating breast cancer without chemotherapy for years - with great success.'

Beyond chemo: Doctors in Austria look very closely at the type of tumour a breast cancer patient has and treat it according to how it's likely to respond

In the UK, the standard treatment for breast cancer is surgery to remove the tumour - and then drugs to reduce the risk of the cancer recurring.
If you're one of the 60 per cent of patients whose cancer is stimulated by the hormone oestrogen, you'll get a drug to block it - most likely Tamoxifen - and then chemotherapy as well. Those patients whose tumours don't respond to hormones just get chemotherapy.
Chemotherapy works by targeting fast-growing cells, such as those in a tumour. Unfortunately, there are many other fastgrowing cells in the body - in the hair, skin, lining the digestive system and the bone marrow (where blood cells are made).
That's why chemotherapy can cause side effects such as nausea, diarrhoea, hair loss, sores in the mouth and throat, and a drop in the number of blood cells that fight infections.
In Austria, cancer specialists look more closely at the type of tumour each patient has - and treat it according to how it's likely to respond. According to Professor Gnant's research, patients there do just as well - if not better - than those who have chemotherapy.

'If a woman had a tumour removed that was very responsive to oestrogen, then I'll probably treat her only with a drug that blocks oestrogen
,' says Professor Gnant, who is based at Vienna Medical University.
In the UK, even if your tumour is very hormone responsive, you are still likely to be given three different types of chemotherapy drugs as well.
The Austrian approach - looking closely at the biology of individual tumours - should become the standard, a major international conference recommended earlier this year.
British experts are aware of this approach, but are more cautious about adopting it.
'It is certainly the way forward,' says Dr Peter Canney, consultant clinical oncologist at the Beatson Cancer Care Centre in Glasgow. 'However, we're not yet good enough at spotting all those who can do without chemotherapy.'
this is not the only innovation in breast cancer care in Austria. To stop cancer returning-some patients are being given bisphosphonates - drugs usually used to treat osteoporosis.

Medicine mix: Some breast cancer patients are given drugs typically used to treat osteoporosis. Pictured is an X-ray of a femur fractured due to the bone-thinning disease

In a recent major trial, published in the New England Journal of Medicine, patients who had just one injection of a high-dose bisphosphonate every six months had a 33 per cent greater chance of remaining cancer-free. So how do bone drugs help with cancer?
'When cells from a breast tumour spread, they often go to the bone,' explains Dr Trevor Powles, a British expert and one of the first oncologists to test the benefits of bisphosphonates on breast cancer. Once they reach the bone, the cancer cells stimulate bone-destroying cells. This, in turn, produces growth factors, which boost the cancer.
'It's a vicious circle,' says Dr Powles. 'Giving a bisphosphonate that kills off the bone-destroying cells actually makes a lot of sense.'

Professor Gnant believes that the evidence for bisphosphonates is good enough for some patients to use it right away.
'If my wife, who hasn't been through the menopause, had cancer, I'd make sure she got it,' he says. 'However, I wouldn't do the same for my mother because the data for post-menopausal women isn't clear yet.'
And the benefits of bisphosphonates may not be limited to breast cancer; they may also improve the treatment of cancers such as lung and prostate. Indeed, it was reported last week that bisphosphonates and breast cancer drugs could destroy cervical cancer.
Professor Gnant believes that as well as migrating into the bone, some cancer cells travel to the bone marrow, where they lurk. This is why the bone drugs could have a much wider benefit.
'Bisphosphonates can affect bone marrow in general, making it less of a sanctuary for the tumour cells so they are less likely to spread,' he says.
So should British patients be seeking this new treatment?
Some experts here, such as Dr Powles at Parkside Oncology Clinic in London, have already been looking at the potential for bisphosphonates.
A few years ago, he conducted a trial giving very high daily doses of oral osteoporosis drugs to more than a 1,000 breast cancer patients and found they improved drug-free survival.
The results from two other trials didn't show the same benefit, so the treatment was not licensed. Now, Gnant's results with a stronger drug (Zometa) may change our approach.
'The results are encouraging, but I'd still want to see some more data,' says Dr Powles.
He and other UK experts are waiting until next year before deciding whether to push for bisphosphonates to be widely used. This is when a bigger UK trial involving about 3,000 patients on higher and more frequent doses of Zometa is due to report.
But could bone drugs replace chemotherapy? Professor Gnant hopes they will at the very least reduce its use. 'Chemotherapy can be a valuable addition to breast cancer treatment, but evidence suggests it can be used more sparingly,' he says.




Zoledronic Acid side effects DISCUSSION



A New Weapon Against Tumor Cells


A new drug could prove to be more effective in cancer treatment as tests show that it is about 200 times more active in killing tumor cells. The active agent comes from a class of drugs called bisphosphonates and it was developed by a team of 24 researches from four countries.
Although they were primarily conceived as a treatment for osteoporosis and other bone diseases, recent discoveries show that bisphosphonates also have inhibitory effects on enzymes such as FPPS and GGPPS, which leads to killing cancer cells with more efficiency that the drugs aimed at the protein Ras (which presents mutations in a third of human cancer cells and represented a less successful target for drug developers).
Derived from bisphosphonates (and used alongside hormonal treatment) the drug zoledronate proved effective in reducing the recurrence of breast cancer in premenopausal women with estrogen-receptor-positive breast cancer and hormone-refractory prostate cancer in men but its efficiency proved diminished by the fact that it binds faster to the bone rather than getting to the tissues where it was needed.
In trying to find a new drug that wouldn’t have this side effect and which would also inhibit more than just one enzyme in the cancer cell’s survival pathway, a new study was carried, led by Professor Eric Oldfield of the University of Illinois. The research team managed to produce drugs that bonded to multiple enzyme targets but not to bone, of which BPH-715 effectively inhibited tumor cell growth and invasiveness and killed tumor cells in mice. BPH-715, as well as zoledronate, also has the effect of increasing the production of gamma delta T-cells, immune system cells that also kill tumor cells.

http://www.topcancernews.com/news/20...mor-cells.html


The sales pitch:
http://www.cancertechnology.com/down...osphonates.pdf



Br J Cancer. 2010 Mar 16. [Epub ahead of print]
The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer.

Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H.
Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Sheffield, UK.
Background:Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups.Methods:In total, 205 patients received neoadjuvant CT+/-ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers.Results:Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5-20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315).Conclusion:These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.British Journal of Cancer advance online publication, 16 March 2010; doi:10.1038/sj.bjc.6605604 www.bjcancer.com.

PMID: 20234364 [PubMed - as supplied by publisher]







Anticancer Res. 2010 May;30(5):1807-13.
Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer.

Rack B, Jückstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W.
Department of Gynecology and Obstetrics, Klinik und Poliklinik fuer Frauenheilkunde und Geburtshilfe, Campus Innenstadt, Ludwig-Maximilians-Universitaet, Muenchen, Germany. brigitte.rack@med.uni-muenchen.de



Abstract

BACKGROUND: There is strong evidence for the isolated tumour cells (ITCs) in the bone marrow of breast cancer patients having prognostic impact both at primary diagnosis and during recurrence-free follow-up. The goal of this study was to investigate the therapeutic efficacy of zoledronate on the persistence of ITC. PATIENTS AND METHODS: A total of 172 primary breast cancer patients without evidence of distant recurrence but detection of ITC in bone marrow were followed up. Zoledronate was administered every 4 weeks for 6 months to 31 patients who had completed surgery and adjuvant chemotherapy. In a matched-pair analysis, these patients were compared to 141 patients who did not receive additional zoledronate treatment. The bone marrow was re-examined after a median of 7.9 months (SD 0.89) and 11.5 months (SD 12.41; p=0.11), respectively. Patients were followed-up prospectively for a median of 39 months after the first aspiration. RESULTS: While ITCs were detected in all 172 patients at the time of first bone marrow aspiration, ITCs were detected in four patients (13%) following 6 months of zoledronate therapy in contrast to 38 patients (27%) of the control group (p=0.099). The reduction in cell numbers between the first and second aspiration reached statistical significance in the zoledronate group (p=0.02 vs. p=0.14). Persistent ITCs at the follow-up aspiration were associated with reduced recurrence-free survival (p=0.05). CONCLUSION: These results indicate a potential antineoplastic effect of the cell cycle-independent agent zoledronate on persisting ITCs in a dormant state.

PMID: 20592383 [PubMed - indexed for MEDLINE]

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thought: There was a study in Britain showing sequencing Zoledronate 24 hrs after doxorubicin had profound anti-cancer effects. Could it be that Dox was somehow redirecting Zol away from bone and to cancer cells?



Int J Cancer. 2010 Jan 15;126(2):522-32.
Sustained inhibition of tumor growth and prolonged survival following sequential administration of doxorubicin and zoledronic acid in a breast cancer model.

Ottewell PD, Lefley DV, Cross SS, Evans CA, Coleman RE, Holen I.
University of Sheffield, United Kingdom.
Combination therapy, using agents that target the microenvironment as well as the cancer cells, is common in the treatment of advanced breast cancer. Here, we show that a 6-week course of weekly sequential administration of the cytotoxic drug doxorubicin (2 mg/kg), followed 24 hr later by the antiresorptive agent zoledronic acid (100 microg/kg), causes substantial inhibition of subcutaneous MDA-MB-436 breast tumor growth in immunocompromised mice, leading to significantly increased survival. Tumor growth did not resume following withdrawal of treatment after 6 weeks, with 60% of the animals in this group surviving for more than 160 days. In comparison, animals receiving single-agent therapy all died within 50 days. Molecular analysis of the tumors showed no effect on cell cycle or apoptosis following administration of 100 microg/kg zoledronic acid or 2 mg/kg doxorubicin alone. When doxorubicin was administered 24 hr before zoledronic acid, tumors displayed decreased expression of CYCLINS E1, B, D1 and D3 as well as CDK2, CDC2, CDK4 and CDK7, indicative of cell-cycle inhibition. Tumors from animals receiving sequential treatment also showed induction of both intrinsic- and extrinsic-apoptotic pathways, with increased expression of BAX, decreased expression of BCL-2 and activation of CASPASE 3, 8 and 9. Accumulation of the unprenylated form of RAP1a, a surrogate marker for uptake of zoledronic acid, was only detected in tumors from animals treated with doxorubicin 24 hr before zoledronic acid. Our data are the first to show a sustained antitumor effect in vivo following a limited course of sequential administration of doxorubicin followed by zoledronic acid.

PMID: 19621384 [PubMed - indexed for MEDLINE]




Mol Cancer Ther. 2009 Oct;8(10):2821-32. Epub 2009 Sep 29.
Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone.

Ottewell PD, Woodward JK, Lefley DV, Evans CA, Coleman RE, Holen I.
Academic Unit of Clinical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
Patients with advanced breast cancer frequently develop bone metastases, and at this stage, the disease is considered incurable. Here, we show that a 6-week course of weekly administration of doxorubicin (2 mg/kg), followed 24 hours later by the bisphosphonate zoledronic acid (100microg/kg), causes substantial inhibition of MDA-MB-436 breast tumor burden in bone of immunocompromised mice, compared with administration of the single agents. Molecular analysis of tumors from animals treated sequentially with doxorubicin followed by zoledronic acid showed reduced numbers of proliferating tumor cells and decreased expression of cyclins E1, B, D1, and D3 as well as cdk2 and cdk4. Tumors from the sequential treatment group also displayed increased levels of apoptosis, increased expression of bcl2-associated X protein, decreased expression of B-cell chronic lymphocytic leukemia/lymphoma 2, and activation of caspase 3, 8, and 9. Zoledronic acid caused a small reduction in tumor volume, reduced tumor cell proliferation, and decreased expression of cyclins D1 and D3, compared with tumors from animals treated with saline or doxorubicin. Doxorubicin had no effect on tumor growth, cell cycle, or apoptosis in vivo, but did cause increased accumulation of a bisphosphonate in MDA-MB-436 cells in vitro, suggesting that doxorubicin may affect subsequent uptake of zoledronic acid. In support of this, accumulation of unprenylated Rap1A, a surrogate marker of zoledronic acid, was only detected in tumors following sequential treatment, and not following treatment with zoledronic acid alone. Our data are the first to show the specific molecular pathways by which sequential treatment with doxorubicin and zoledronic acid induce tumor cell apoptosis and inhibit proliferation in an in vivo model of breast tumor growth in bone.

PMID: 19789217 [PubMed - indexed for MEDLINE]





1: J Natl Cancer Inst. 2008 Aug 20;100(16):1167-78. Epub 2008 Aug 11. Links

Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer.

Ottewell PD, Mönkkönen H, Jones M, Lefley DV, Coleman RE, Holen I.
Academic Unit of Clinical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. i.holen@sheffield.ac.uk.
BACKGROUND: The potent antiresorptive drug zoledronic acid (Zol) enhances the antitumor effects of chemotherapy agents in vitro. We investigated the effects of clinically achievable doses of doxorubicin (Dox) and Zol, given alone, in sequence, and in combination, on the growth of established breast tumors in vivo. METHODS: Female MF1 nude mice were inoculated subcutaneously with 5 x 10(5) human breast cancer MDA-MB-436 cells that stably expressed green fluorescent protein (ie, MDA-G8 cells). Beginning on day 7 after tumor cell injection, the mice were injected weekly for 6 weeks with saline, Dox (2 mg/kg body weight via intravenous injection), Zol (100 microg/kg body weight via intraperitoneal injection), Dox plus Zol, Zol followed 24 hours later by Dox, or Dox followed 24 hours later by Zol (n = 8-9 mice per group). The effects of treatment on tumor growth were determined by measuring tumor volume; on tumor cell apoptosis and proliferation by immunohistochemistry using antibodies for caspase-3 and Ki-67, respectively; and on bone by microcomputed tomography and bone histomorphometry. All P values are two-sided. RESULTS: Treatment with Dox or Zol alone or Zol followed 24 hours later by Dox did not statistically significantly decrease final tumor volume compared with saline. Mice treated with Dox plus Zol had statistically significantly smaller final tumor volumes than those treated with Dox alone (mean = 122 mm(3) vs 328 mm(3), difference = 206 mm(3), 95% confidence interval [CI] = 78 to 335 mm(3), P < .001), with Zol alone (122 mm(3) vs 447 mm(3), difference = 325 mm(3), 95% CI = 197 to 454 mm(3), P < .001), or with Zol followed 24 hours later by Dox (122 mm(3) vs 418 mm(3), difference = 296 mm(3), 95% CI = 168 to 426 mm(3), P < .001). Treatment with Dox followed 24 hours later by Zol almost completely abolished tumor growth. Tumors from mice that were treated with Dox followed by Zol had more caspase-3-positive cells than tumors from mice treated with saline (mean number of caspase-3-positive cells per square millimeter: 605.0 vs 82.19, difference = 522.8, 95% CI = 488.2 to 557.4, P < .001), with Zol alone (605.0 vs 98.44, difference = 506.6, 95% CI = 472.0 to 541.2, P < .001), or with Zol followed by Dox (605.0 vs 103.1, difference = 501.9, 95% CI = 467.3 to 536.5, P < .001). The treatment-induced increase in the number of caspase-3-positive cells was mirrored by a decrease in the number of tumor cells positive for the proliferation marker Ki-67. No evidence of bone disease was detected in any of the treatment groups following microcomputed tomography and histological analysis of bone. CONCLUSION: Sequential treatment with Dox followed by Zol elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease.
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Br J Cancer. 2010 Feb 16. [Epub ahead of print]
Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction.

TEXT

Neville-Webbe HL, Coleman RE, Holen I.
Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield S10 2SJ, UK.
Background:Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed.Methods:Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter.Results:We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone.Conclusion:Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.British Journal of Cancer advance online publication, 16 February 2010; doi:10.1038/sj.bjc.6605579 www.bjcancer.com.

PMID: 20160726 [PubMed - as supplied by publisher]

Quote:
In combination, ZA and letrozole have potential for synergistic induction of MCF7-Ca cells in vitro. However, increased induction of apoptosis only occurred when cells were treated with letrozole followed by ZA. ‘Letrozole then ZA’ induced a level of apoptosis that was over eight times greater than that caused by letrozole alone, and 4.8 times greater than treatment with ZA alone. The ZA has consistently shown potential for synergistic interaction with drugs commonly used in breast cancer. This includes a
combination with paclitaxel (Jagdev et al, 2001; Neville-Webbe et al, 2006), tamoxifen (Jagdev et al, 2000) and doxorubicin (Neville-Webbe et al, 2005).
In our earlier study with ZA and chemotherapy drugs, we have similarly found that sequential administration of drugs is of paramount importance for inducing maximal (potentially synergistic) levels of apoptosis. For breast cancer cells treated with ZA in combination with either doxorubicin or paclitaxel, as with letrozole, cells had to be treated with the chemotherapy drug first, and thereafter with ZA. Treating cancer cells with the reverse sequence, or even simultaneously, was either antagonistic or, at best, additive, and the same patterns were seen here with letrozole. Our group recently evaluated this
sequence-dependent synergy in an in vivo soft-tissue breast tumour model (Ottewell et al, 2008a, b). Using clinically relevant doses of doxorubicin and ZA, inhibition of tumour growth was shown to be sequence dependent with doxorubicin followed by ZA,
leading to inhibition of tumour growth associated with evidence of enhanced tumour cell apoptosis and reduced proliferation.
The biological effects of letrozole and ZA are largely mediated through the induction of apoptosis. It is likely that this is enhanced through inhibition of the mevalonate pathway. Using an intermediary of this pathway (GGOH), apoptosis was reduced by 50% for cells treated with the sequence ‘ letrozole then ZA’. Inhibition of the mevalonate pathway by nitrogen-bisphosphonates is integral for inducing a variety of effects including apoptosis of osteoclasts (Amin et al, 1992), breast cancer cells (Jagdev et al, 2001), prostate cancer cells (Oades et al, 2003), myeloma cells (Shipman et al, 1998) and inhibition of tumour cell invasion (Denoyelle et al, 2003). Furthermore, inhibition of this pathway also contributes to the apoptosis induced when breast (and prostate) cancer cells are treated in combination with ZA and doxorubicin (Neville-Webbe et al, 2005), or when breast cancer cells are treated with ZA and paclitaxel (Neville-Webbe et al, 2006).
Although in vitro and in vivo studies have limited implications for the clinical setting, it is interesting to note a recent update of the ZO-FAST study (Eidtmann et al, 2008). This clinical trial assesses the effects of ZA on letrozole-induced bone loss in postmenopausal
women with early breast cancer. Patients are randomised to either combined letrozole and ZA (4 mg every 6 months) or letrozole alone. A recent update, with a 36-month
follow-up, suggested a better outcome for those treated with the combination, with a 41% risk reduction in cancer recurrence. Although these results are preliminary, and the trial was not specifically set up to address the anti-tumour potential of ZA in patients
receiving letrozole, they add to the growing evidence of the direct anti-cancer effects of this bisphosphonate in combination with other drugs, including endocrine treatments.
Similarly, in the ABCSG 12 trial of pre-menopausal breast cancer patients (Gnant et al, 2009), 1803 patients received ovarian suppression with goserelin and were then randomised to receive either tamoxifen or the AI anastrazole, with or without ZA (4mg infusions every 6 months for 3 years). No significant differences in disease-free survival were seen between tamoxifen and AI. However, the group receiving ZA had a statistically significant 36% reduction in the risk of disease recurrence, compared with patients receiving endocrine therapy alone (P¼0.01). The reduction in metastatic events was not confined to a reduction in the frequency of bone metastases alone,
but also applied to distant metastatic sites, loco-regional recurrence rates and cancer of contralateral breast. Reduction of metastases outside the skeleton adds to the growing evidence that the antitumour effects of ZA are not confined to the bone, and such antitumour effects may be enhanced by combination with other drugs.

In summary, letrozole has anti-tumour activity (which is largely through induction of apoptosis) when used alone under culturemedia conditions that mimic the post-menopausal state. When combined with ZA, there is potential for a synergistic induction of apoptosis, but only when cancer cells are treated with letrozole followed by ZA. This may have positive implications for postmenopausal patients receiving both these drugs in the clinical setting.
Quote:
Though not reproducible using a very low concentration of ZA, synergy is induced with 10 mM, a concentration that could be achieved within the bone microenvironment.


Breast Cancer Res. 2006;8(4):R52.
In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells.

FULL TEXT


Ural AU, Avcu F, Candir M, Guden M, Ozcan MA.
Department of Hematology, Gulhane Military Medical Faculty, Ankara, Turkey. aural@gata.edu.tr
INTRODUCTION: Bisphosphonates are mostly used in the treatment of bone metastases. They have been shown to act synergistically with other chemotherapeutic agents. It is not known, however, whether similar synergistic effects exist with radiation on breast cancer cells. METHODS: Human MCF-7 breast cancer cells were treated with up to 100 microM zoledronic acid, were irradiated with up to 800 cGy or were exposed to combinations of both treatments to determine the antiproliferative effects of zoledronic acid and radiation. RESULTS: Zoledronic acid and radiation caused a dose-dependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 microM and 20 microM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). A synergistic cytotoxic effect of the combination of zoledronic acid and radiation was confirmed by isobologram analysis. CONCLUSION: These data constitute the first in vitro evidence for synergistic effects between zoledronic acid and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with metastatic breast carcinoma.

PMID: 16925824 [PubMed - indexed for MEDLINE]




pn J Clin Oncol. 2009 Nov;39(11):745-50. Epub 2009 Oct 6.
A case of bone, lung, pleural and liver metastases from renal cell carcinoma which responded remarkably well to zoledronic acid monotherapy.


Miwa S, Mizokami A, Konaka H, Izumi K, Nohara T, Namiki M.
Department of Integrative Cancer Therapy and Urology, 13-1 Takara-machi, Kanazawa City 920-8640, Japan.
Herein, we report a rare case in which bisphosphonate zoledronic acid (ZA) effectively treated not only multiple bone metastases but also lung, pleural and liver metastases from renal cell carcinoma (RCC). Recently, ZA is used to treat skeletal-related events (SREs) such as bone pain caused by bone metastasis from many kinds of cancer. The patient in the present report had multiple bone metastases from RCC. Remarkable improvement of the bone metastasis was observed following treatment with ZA at a dosage of 4 mg administered once every 4 weeks. Moreover, lung, pleural and liver metastases also diminished markedly in size in response to the treatment. The metastases have shown no progression for 20 months since starting the ZA treatment. We believe that the present report is the first of its kind announcing that ZA monotherapy has been effective for lung, pleural and liver metastases from RCC.



J Exp Clin Cancer Res. 2010 Jul 30;29:102.
Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer.

Karabulut B, Karaca B, Varol U, Muslu U, Cakar B, Atmaca H, Kisim A, Uzunoglu S, Uslu R.
Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey.


FREE TEXT

Abstract

BACKGROUND: Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All- trans retinoic acid (ATRA) induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events.
METHODS: XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR), myeloid cell leukemia-1 (MCL-1), tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), TNFRSF1A-associated death domain protein (TRADD).
RESULTS: We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited.
CONCLUSIONS: These are the preliminary molecular results of a novel combination treatment of ATRA and zoledronic acid, with fewer side effects as compared to conventional cytotoxic agents. With additional experimental analysis, it may serve as a good option for the treatment of refractory and elderly ovarian cancer patients, for whom there exists very limited choice of treatment.

PMID: 20673323 [PubMed - in process]PMCID: PMC2924277Free PMC Article


Mol Biol Rep. 2010 Mar 28. [Epub ahead of print]
Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines.

Karabulut B, Karaca B, Atmaca H, Kisim A, Uzunoglu S, Sezgin C, Uslu R.
Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey.
TEXT

AbstractWe report that all-trans retinoic acid (ATRA) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells, PC-3 and DU-145, in a time- and dose-dependent manner. We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells, in which the drug combination shows much more strong synergistic effects, as compared to PC-3 cells. Moreover, we have also performed real time-PCR array analysis to validate oligoarray results. We demonstrated that the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145, at either transcriptional or translational levels. While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), Bad, Bax, Fas, FADD are induced with the exposure of the combination, expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family (IAPs), MCL-1, LTBR, p53 and bcl-2 are reduced. Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents, this regimen may be a good option for treatment of elderly prostate cancer patients.

PMID: 20349282 [PubMed - as supplied by publisher]






Int J Urol. 2009 Sep;16(9):726-31; discussion 731-2.
Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: factors predicting response and survival.

Nayyar R, Sharma N, Gupta NP.
Department of Urology, All India Institute of Medical Sciences, New Delhi, India.
OBJECTIVES: To evaluate the efficacy of docetaxel/prednisone and zoledronic acid in hormone refractory prostate cancer (HRPC) patients and to analyze prognostic factors predicting overall survival. METHODS: Forty-four HRPC patients were given docetaxel (75 mg/m(2)), prednisone and zoledronic acid (4 mg) every three weeks. Overall and progression-free survival curves were calculated. Using the log-rank test, variables predicting overall survival (age, Gleason score, baseline prostate-specific antigen [PSA], percentage PSA decline, nadir PSA, number of chemotherapy cycles) were calculated. RESULTS: Median age was 66 years and mean PSA 171.25 ng/mL. The average number of given cycles was 6.3. A good PSA response (>50% decline) was observed in 26/44 cases (59.1%). A total of 17/44 (38.6%) patients expired with a median overall survival of 62.4 weeks. Patients with a Gleason score less than 7, who received more than four cycles and with a more-than-50% decline in PSA had significantly better survival. Variables like age, baseline PSA and nadir PSA did not significantly affect survival. CONCLUSION: The combination of docetaxel/zoledronic/prednisone is safe and effective in the management of HRPC. Patients with a Gleason score <7, PSA decline >50% and those who receive more than four cycles have significantly better survival.

PMID: 19769656 [PubMed - in process]





Possibly overlooked toxicity labeling, 4mg maximum:
FDA Drug Information That Never Reaches Clinicians
http://content.nejm.org/cgi/content/.../561?query=TOC
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Old 05-24-2009, 10:11 PM   #4
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Hmmm...have a subscription????

Annals of Oncology Advance Access originally published online on March 5, 2009
Annals of Oncology 2009 20(4):796-797; doi:10.1093/annonc/mdp026

© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

letters to the editor


Zoledronic acid-induced regression of multiple metastases at nonskeletal sites

The first 10% of the full text of this article appears below.
Bisphosphonates have been shown to reduce skeletal complications in individuals with bone metastases secondary to a wide range of solid tumors including lung, breast, and prostate cancer [1]. They are widely administered as palliative agents together with chemotherapy, hormonal therapy, or irradiation [2]. In addition, several types of cancer cells including hematologic malignancies respond to bisphosphonates in . . . [Full Text of this Article]
K. Okamoto, J. Tsurutani*, M. Terashima, I. Okamoto and K. Nakagawa
Department of Medical Oncology, Kinki University School of Medicine, Osakasayama, Osaka, Japan
* (E-mail: tsurutani_j@dotd.med.<b><font color=.../b>indai.ac.jp)


Full Text

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Old 05-24-2009, 10:18 PM   #5
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Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation




Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands, and Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
J. Am. Chem. Soc., 2009, 131 (14), pp 5153–5162
DOI: 10.1021/ja808285e
Publication Date (Web): March 23, 2009
Copyright © 2009 American Chemical Society
† Department of Chemistry, University of Illinois at Urbana−Champaign.

, ‡ Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign.

, § Institute of Biological Chemistry, Academia Sinica.

, Department of Biology, Brookhaven National Laboratory.

, Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center.

, # Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University.

, eo@chad.scs.uiuc.edu


Abstract


Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.


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Br J Cancer. 2007 May 21;96(10):1526-31. Epub 2007 Apr 17.
Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer.

FULL TEXT (free)





Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G.
Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2.
Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

PMID: 17437017 [PubMed - indexed for MEDLINE]
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Curr Opin Rheumatol. 2010 May 13. [Epub ahead of print]
Bisphosphonate adverse effects, lessons from large databases.

Abrahamsen B.
aCopenhagen University Hospital Gentofte, Department of Medicine Internal Medicine and Endocrinology F, Niels Andersensvej 65, DK-2900 Hellerup, Denmark bUniversity of Southern Denmark, Institute of Clinical Research, Odense Patient Data Exploratory Network (OPEN), Winslowparken 16, 3., DK-5000 Odense C, Denmark.
Abstract

PURPOSE OF REVIEW: To review the latest findings on bisphosphonate safety from health databases, in particular sources that can provide incidence rates for stress fractures, osteonecrosis of the jaw (ONJ), atrial fibrillation and gastrointestinal lesions including esophageal cancer. The main focus is on bisphosphonates used for osteoporosis. RECENT FINDINGS: Register studies have so far not confirmed a shift from classical to nonclassical femur fractures with bisphosphonates. However, studies were either small or without X-ray adjudication. Two new studies found no increase in jaw surgery for inflammatory conditions - a proxy for ONJ - with oral bisphosphonates, but the risk of jaw necrosis was increased almost eight times in those receiving i.v. bisphosphonates. The risk of atrial fibrillation with alendronate may be increased in the first weeks of treatment, but no excess risk was seen in long-term users. Two studies have found decreased risk of esophageal cancer in patients taking oral bisphosphonates. SUMMARY: Compared with the reduction in classical osteoporotic fractures, the risk of harm caused by bisphosphonates is low, according to information presently available from clinical trials and from health databases. However, database studies have limited specificity and sensitivity for atypical fractures and ONJ. Clinical case control studies are recommended.
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Old 06-03-2009, 11:12 AM   #7
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BPH-715 is apparently far from being available in trials. Zoledronate is said to be the best currently available bisphosphonate in this sense.
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Old 06-05-2009, 07:44 PM   #8
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Effects of zoledronic acid (ZOL) on proliferation of nasopharyngeal carcinoma (NPC) cell lines and synergistic effects of ZOL and cisplatin on NPC cell lines.


Sub-category: Cytotoxic Chemotherapy
Category: Developmental Therapeutics: Cytotoxic Chemotherapy
Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27, 2009 (suppl; abstr e13536)
Abstract No: e13536
New this year -- Publication-only abstracts (abstract number preceded by an 'e'), are published in conjunction with the 2009 Annual Meeting but not presented at the Meeting, can be found online only.

The publication-only abstracts are not included in the print or CD versions of the ASCO Annual Meeting Proceedings Part I, but they are citable to this issue of the Journal of Clinical Oncology as a supplement (see citation on left).


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Author(s): B. R. Ghimire; Om Hospital and Research Centre, Kathmandu, Nepal

Abstract:
Background: Recent evidence suggests that zoledronic acid (ZOL) inhibits cancer cell proliferation and exerts synergistic antitumor activity at clinically achievable concentrations and have shown the potential to become attractive agents for cancer therapy. This study is the first to report the effects of ZOL on NPC cell lines. Methods: Cell proliferations were determined by MTT assay on four NPC cell lines CNE-1, CNE-2, SUNE-1 and 5-8F. NPC cell lines were seeded in a flat-bottomed 96well plate at 10+4 in 200µl of medium per well and incubated with various concentrations of ZOL for 72 hours. IC50 values for each cell lines were obtained using the non-linear regression program CalcuSyn. IC10 values for ZOL and Cisplatin were calculated from the IC50 curve of each four cell lines. For displaying the synergistic activity concentration equivalent to IC10 of ZOL alone, Cisplatin alone and in combination were added. The entire specimen was incubated for a total of 72 hours and the absorbance was measured at a wavelength of 540nm in a multiwell spectrophotometer. Results: IC5O values (µM) of ZOL on NPC cell lines SUNE-1, CNE-1, CNE-2, 5-8F were 4.56±0.09, 11.96±0.50, 16.73±0.28, 11.01±0.64 respectively. Conclusions: The experiment establishes synergistic effects of ZOL and cisplatin in anti proliferation of NPC cell lines. Thus, ZOL in combination with other cytotoxic agents may be promising therapeutic strategies for NPC with bone metastasis. The efficacy and safety of ZOL for NPC should be verified in early phase clinical trials




Inhibition of proliferation (%) when ZOL and cisplatin used alone and in combination

Cell linesConcentration of
drugs used ZOL(µM)
and cisplatin (µM)
respectively
Combination
of ZOL and
cisplatin
ZOL aloneCisplatin alone

SUNE-10.9 and 0.463.33±3.02%13.44±8.02%14.36±8.67%
CNE-12.8 and 0.4163.95±5.5%13.61±6.96%13.61±5.33%
CNE-23 and 0.842.29±1.96%14.30±3.00%14.93±2.37%
5-8F2.2 and 0.560.61±7.5%10.37±5.8%11.35±6.8%

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Old 06-17-2009, 11:51 AM   #9
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Why only in HR-? Maybe because not sequenced 24hrs after chemo. No mention of Her2 status but here it is:


From Reuters Health Information

Bisphosphonates May Prolong Survival in Metastatic Breast Cancer Patients

By David Douglas
NEW YORK (Reuters Health) Jun 15 - IV bisphosphonate in addition to chemotherapy or hormonal therapy has an anti-tumor effect on hormone receptor (HR)-negative breast cancer patients with bone metastases, who may gain a survival advantage, according to Korean researchers.
Because of the retrospective nature of the study, investigator Dr. Jungsil Ro told Reuters Health, "we cannot strongly claim prolonged survival. However, the data appear encouraging enough to design a prospective study to confirm the anti-tumor activity of IV bisphosphonate."
In a May 20th paper published in BMC Cancer, Dr. Ro and colleagues at the National Cancer Center, Goyang-si point out that bisphosphonates have become the standard therapy for breast cancer patients with bone metastasis. This treatment reduces the symptoms and complications of bone involvement. However, the clinical relevance of their anti-tumor effect has not been established.
To gain more information, the researchers studied data on 230 patients with HR-positive tumors and 87 with HR-negative tumors. All had bone metastasis at diagnosis and known breast cancer subtypes.
Most of the women (n=262; 82.6%) received therapy with bisphosphonates during follow-up. The median number of cycles of treatment was 17.7 and the median interval between cycles was 31 days.
No survival benefit was seen in HR-positive patients, but HR-negative patients receiving bisphosphonates showed significantly improved survival (hazard ratio, 0.56). Median overall survival was 1.7 years in HR-negative patients who received bisphosphonates compared with 1.3 years in HR-negative patients who did not receive bisphosphonates.
Multivariate analysis showed that in HR-negative patients, bisphosphonate was a significant overall survival factor. More bisphosphonate-treated HR-negative women also had disease-free intervals of more than 2 years and fewer than three metastatic sites.
The researchers conclude that bisphosphonate treatment "may give a survival benefit in metastatic breast cancer patients, particularly in patients with HR-negative tumors, which are known to have a poorer prognosis."
"We have designed a prospective study in metastatic breast cancer patients without bone metastasis to see whether IV bisphosphonate -- zoledronic acid -- in combination with chemo- or hormone therapy as a first-line therapy will show an anti-tumor effect... or decrease bone metastasis," Dr. Ro added.
BMC Cancer 2009;9.



From a researcher regarding relevancy of ER status:

I am afraid I will not be able to scientifically resolve this. All I can say is that the Korean study was done in patients with bone metastases, and neither ZA treatment nor receptor status served as a prospectively defined factor in any way. This limits the power of that report to support its conclusion, and - as always in such retrospective investigations - the result they obtained may well be observed just by chance. I would not draw the conclusion that ZA is not effective in HR-positive breast cancer.


In fact, in the early disease setting, the contrary appears to be true. As we have shown in the ABCSG-12 trial you are refering to (NEJM Feb 12, 2009), ZA can decrease the risk of relapse in the aduvant setting in a trial of endocrine responsive premenopausal breast cancer patients by about 36 per cent. This report was confirmed by the 3-year results of the bone protection ZO-FAST trial in postmenopausal patients, also exclusively done in patients with endocrine-responsive breast cancer. We are currently lacking data on receptor-negative breast cancer in the adjuvant setting. This patient population is studied in the AZURE trial, which is due to report by the end of 2010.


In summary, I dont think that currently we have any reason to believe that ZA would be less effective in endocrine-responsive breast cancer. As far as I know, all data on preventing and delaying SREs in patients with bone metastases by ZA have been obtained in a receptor-unstratified patient population
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Old 06-21-2009, 11:00 PM   #10
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Cancer Res. 2010 Jun 15;70(12):5014-23. Epub 2010 May 25.
Reversal of chemotherapy-induced leukopenia using granulocyte macrophage colony-stimulating factor promotes bone metastasis that can be blocked with osteoclast inhibitors.

Dai J, Lu Y, Yu C, Keller JM, Mizokami A, Zhang J, Keller ET.
Department of Urology, University of Michigan, Ann Arbor, Michigan 48109-8940, USA.



Abstract

Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF-induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy.

PMID: 20501834 [PubMed - in process]PMCID: PMC2888854 [Available on 2011/6/1]

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Old 06-22-2009, 03:32 PM   #11
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1: Eur J Clin Invest. 2009 Jun 12. [Epub ahead of print] Links
Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells.

Petrini I, Pacini S, Petrini M, Fazzi R, Trombi L, Galimberti S.
Department of Oncology, Transplant and New Advances in Medicine, University of Pisa and RRMR-CUCCS Regione Toscana, Pisa, Italy.
Eur J Clin Invest 2009Abstract Background
Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T- and B-lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma/delta T cells has still not been evaluated. Gamma-delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft-vs.-host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes. Materials and methods Peripheral blood mononuclear cells from 21 healthy donors were used as source for gamma-delta T cells, expanded in presence of 10 IU mL(-1) interleukin-2 (IL-2) and 1 muM zoledronate. MSCs were recovered from patients undergoing routine total hip replacement surgery, and characterised by flow cytometry. Cytotoxicity on multiple myeloma and melanoma cell lines was assessed by measuring dilution of the carboxyfluorescein diacetate succinimydylester dye (CFSE). Gamma-delta T cells were then incubated with MSCs in contact cultures, and with addition of MSC-conditioned medium. Results In this article we confirmed that (1) in vitro expanded gamma-delta T cells play a significant anti-proliferative effect on multiple myeloma and melanoma cells and (2) multipotent mesenchymal stromal cells effectively suppress the ex vivo expansion of T cells carrying a specific T-cell receptor gene (TCR) rearrangement, Vgamma9/Vdelta2, induced by the combination of IL-2 and zoledronate, without interfering with their cytotoxic activity. Discussion These findings contribute to explain the activity of ex vivo expanded mesenchymal cells, suggesting that MSCs would interact with gamma-delta T lymphocytes. Conclusion This effect could be relevant in separating graft-vs.-host from the graft-vs.-tumour effect, especially considering the possibility of modulating T-lymphocytes activity by the immunomodulating drugs now available.
PMID: 19522834 [PubMed - as supplied by publish

Cancer Res. 2007 Aug 1;67(15):7450-7.
Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer.

Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D'Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC.
Dipartimento di Biopatologia e Metodologie Biomediche, UniversitÃ* di Palermo, Palermo, Italy. dieli@unipa.it
The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma.

PMID: 17671215 [PubMed - indexed for MEDLINE]
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Old 06-22-2009, 03:36 PM   #12
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http://clincancerres.aacrjournals.or...ull/13/22/6850

Letters to the Editor

Zoledronic Acid and Angiogenesis

Gianluigi Ferretti, Alessandra Fabi, Paolo Carlini, Paola Papaldo, Alessandra Felici, Silverio Tomao and Francesco Cognetti Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
To the Editors: In a recent issue of Clinical Cancer Research, Santini and co-workers (1) assert that zoledronic acid (ZA) may inhibit several antiangiogenic-related cascades and its metronomic administration could represent a new potential therapy targeting the endothelial-tumor-stroma behavior. We agree with the authors because better targeting of ZA to cells outside bone could more likely be achieved by more frequent administration of low doses. Thus, metronomic ZA administration could lead to significant intracellular accumulation over time in tumor cells (2).
In cervical tumors, the antineoplastic responses due to impaired angiogenesis and reduced vascularity could result in part from the targeting of matrix metalloproteinase (MMP)-9. MMP-9 could mobilize vascular endothelial growth factor (VEGF) and increase its association with VEGF receptor-2. ZA suppresses MMP-9 expression by tissue-infiltrating macrophages and inhibits its activity, reducing association of VEGF with its receptor on angiogenic endothelial cells (3). In mice, a combinatorial regimen involving a MMP inhibitor along with metronomic chemotherapy produced regression and survival benefit against large end-stage pancreatic tumors. On the other hand, ZA can also directly inhibit proliferation of the angiogenic endothelial cells. Bisphosphonates, however, have been used in animal models at high doses, which are not comparable with the clinical dosing regimens used for the treatment of cancer patients with skeletal metastases (4).
With regard to the ability of ZA to inhibit MMP-9, it is worthwhile noting that MMP-9 is involved in mobilization of circulating endothelial progenitor cells and hematopoietic stem cells from the bone marrow. MMP-9 induced in bone marrow cells causes the conversion of Kit ligand from a membrane-bound, adhesion/survival-promoting molecule to a soluble survival/motogenic molecule, releasing soluble Kit ligand and permitting the transfer of endothelial and hematopoietic stem cells from the quiescent to proliferative niche (5). Release of soluble Kit ligand by MMP-9 enables bone marrow repopulating cells to translocate to a permissive vascular niche, favoring differentiation and reconstitution of the stem/progenitor cell pool. The mobilization of both hematopoietic stem cells and VEGF receptor-2–expressing circulating endothelial progenitor cells to the circulation occurs in response to VEGF and is MMP-9 dependent (5). MMPs and the VEGF/VEGF receptor-2 system are responsible not only for the formation of the dense vascular network but also for the recruitment and infiltration of bone marrow–derived macrophages. Depleting tumor-associated macrophages and tumor-associated dendritic cells, however, does not eliminate other stromal sources of proangiogenic mediators (i.e., mast cells, neutrophils, fibroblasts, other dendritic cell subsets, and possibly pericytes). For this reason, tumor-associated macrophage depletion remains an adjuvant treatment that has to be combined with chemotherapy or radiotherapy.
References

  1. Santini D, Vincenzi B, Galluzzo S, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 2007;13:4482–6.[Abstract/Free Full Text]
  2. Ferretti G, Fabi A, Carlini P, Papaldo P, Felici A, Cognetti F. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. Bone 2007;41:155–6.[Medline]
  3. Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 2004;114:623–33.[CrossRef][Medline]
  4. Clézardin P, Ebetino FH, Fournier PGJ. Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 2005;65:4971–4.[Abstract/Free Full Text]
  5. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625–37.[CrossRef][Medline]

Related Article

Zoledronic Acid and Angiogenesis
Daniele Santini, Bruno Vincenzi, and Giuseppe Tonini
Clin. Cancer Res. 2007 13: 6850-6851. [Full Text] [PDF]
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Old 06-23-2009, 01:23 PM   #13
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Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer
http://content.nejm.org/cgi/content/abstract/360/7/679
ABSTRACT
Background Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties.
Methods We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points.
Results After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles.
Conclusions The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646 [ClinicalTrials.gov] .)


critiques/responses:

http://content.nejm.org/cgi/content/full/360/22/2367

The author replies: In response to Wenz, Gelber and Aebi, Katz et al., Li and Dong, and Reimer and Gerber: according to St. Gallen and National Comprehensive Cancer Network guidelines, goserelin plus tamoxifen is an accepted treatment for premenopausal patients with endocrine-responsive breast cancer, and luteinizing hormone–releasing hormone agonists alone are associated with a strong trend toward reduced rates of recurrence and death.1 In the ABCSG-12 study, the selection of 3 years of endocrine therapy was based on the findings of the ABCSG-5 trial (ClinicalTrials.gov number, NCT00309478 [ClinicalTrials.gov] ) (which examined 3 years of goserelin, then 5 years of tamoxifen).2 However, 5 years of continuous endocrine therapy may not be necessary in this low-risk population, since it would be difficult to improve the 98.2% 4-year overall survival achieved in the group receiving zoledronic acid in the ABCSG-12 trial. We agree that long-term follow-up of SOFT and Triptorelin with Exemestane on Tamoxifen (TEXT) (NCT00066703 [ClinicalTrials.gov] ) may provide more definitive guidance on the use of aromatase inhibitors in premenopausal patients with breast cancer.
The ABCSG-12 study was designed and powered to show whether the addition of zoledronic acid to endocrine therapy improved outcomes, as compared with endocrine therapy alone. A specific interaction test did not reveal any difference in the treatment effect between the group receiving anastrozole plus zoledronic acid and the group receiving tamoxifen plus zoledronic acid. Therefore, at this time, it is not possible to conclude that the effect of zoledronic acid was driven primarily by the findings in one cohort. Longer follow-up of the zoledronic acid effect may help to determine whether meaningful differences exist.
Reimer and Gerber are correct in pointing out that there was a nonsignificant trend favoring tamoxifen over anastrozole for survival, and both P values in Figure 2E should be 0.07 rather than 0.70. (The article has been corrected at NEJM.org.)
In response to Li and Dong: we did not prospectively determine the HER-2/neu status of patients in our study. However, since patients underwent randomization, the proportion of HER-2/neu–positive patients is likely to have been balanced among the study groups and is unlikely to have confounded the trial outcomes.
In response to Berruti et al.: vitamin D levels and vitamin D supplementation were not part of our protocol and therefore were not prospectively recorded. However, we agree that this could be an important factor and should be elucidated in future trials of adjuvant bisphosphonates.
We agree with De Luca and Normanno that the antitumor effects of zoledronic acid may be mediated by preventing the secretion of angiogenic factors by mesenchymal stem cells in bone marrow. This is entirely consistent with the idea that zoledronic acid makes the bone-and-marrow microenvironment less favorable "soil" for tumor-cell growth. One hypothesis is that bone may provide a sanctuary for dormant micrometastases that may later seed distant metastases. Preliminary clinical data suggest that the antitumor activity of zoledronic acid may include the inhibition of angiogenesis, immunostimulatory effects through the activation of gamma delta T cells,3 and a reduction in the number of disseminated tumor cells in bone marrow.4 In addition, recent results from the neoadjuvant subgroup analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) (NCT00072020 [ClinicalTrials.gov] ) trial indicate that zoledronic acid has direct antitumor activity.5 Therefore, stimulation of a wide array of antitumor effects by zoledronic acid may inhibit disease progression in areas other than bone in patients with breast cancer.
Michael Gnant, M.D.
Medical University of Vienna
A-1090 Vienna, Austria
michael.gnant@meduniwien.ac.at
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Old 06-23-2009, 01:52 PM   #14
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Are there any papers/trials/research out there showing that HER-2+/HR- patients would benefit from taking Zoledronate together with or after their year of Herceptin to prevent bone mets or recurrence in general?

Thanks!
__________________
ER+ (30%)/PR-/HER-2+, stage 3

Diagnosed on 02/18/09 at 38 with a huge 12x10 cm tumor, after a 6 month delay. Told I was too young and had no risk factors. Found swollen node during breastfeeding.
March-August 09: neo-adjuvant chemo, part of a trial at Stanford (4 DD A/C, 4 Taxotere with daily Tykerb), loading dose of Herceptin
08/12/09 - bye bye boobies (bilateral mastectomy)
08/24/09 - path report shows 100 % success in breast tissue (no cancer there, yay!), 98 % success in lymphatic invasion, and even though 11/13 nodes were still positive, > 95 % of the tumor in them was killed. Hoping for the best!
September-October 09: rads with daily Xeloda
02/25/10 - Cholecystectomy
05/27/10 - Bone scan clear
06/14/10 - CT scan clear, ovarian cyst found
07/27/10 - Done with Herceptin!
02/15/11 - MVA-BN HER-2 vaccine trial
03/15/11 - First CA 15-3: 12.7 and normal, yay!
10/01/11 - Bone scan and CT scan clear, fatty liver found
now on Tamoxifen and Aspirin


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Old 06-29-2009, 02:45 PM   #15
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Oncology. 2006;70(2):147-53. Epub 2006 Apr 26.
Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents.

Budman DR, Calabro A.
Section of Experimental Therapeutics, Don Monti Division of Oncology, North Shore University Hospital, New York University, Manhasset, 11030, USA. budman@nshs.edu

LINK

Abstract

OBJECTIVES: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro.
METHODS: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic.
RESULTS: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied.
CONCLUSIONS: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.

PMID: 16645328 [PubMed - indexed for MEDLINE]



J Clin Immunol. 2010 Sep;30(5):766-74. Epub 2010 Jun 15.
Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells.

Su X, Zhang L, Jin L, Ye J, Guan Z, Chen R.
Biomedical Research Center, The First Hospital of Kunming, Kunming 650011, People's Republic of China. suxs163@163.com
LINK


Abstract

INTRODUCTION: Dendritic cells (DCs) have greater stimulating activity on innate and adaptive immunity following short-term sensitization with zoledronate acid (DCs(Zol)). We identified the phenotype, cytotoxicity, and mechanisms of killing of cytokine-induced killer (CIK) cells which were cocultured with DCs(Zol).
METHODS: Adherent and nonadherent cells of peripheral blood mononuclear cell from myeloma patients were incubated for DCs and CIK cells. Then, the CIK cells were cocultured with DCs(Zol) (DCs(Zol)-CIK). Expression of markers for DCs(Zol)-CIK cells was measured using flow cytometry. Cytotoxicity was evaluated by against human myeloma cell lines and mechanisms of killing were tested by selectively blocking NKG2D receptor. The anti-tumor activity of these effector cells was further evaluated using a nude mice tumor model.
RESULTS: gammadelta TCR expression of CIK cells significantly increased after coculture with immature or mature DCs(Zol) (iDCs/mDCs(Zol)-CIK) and these cells aggressively lysed myeloma cells compared with mDCs-CIK and zoledronate acid pulsed CIK cells (CIK(Zol); 50.8 +/- 7.9% and 48.2 +/- 4.7% versus 31.9 +/- 5.1% and 20.5 +/- 3.6%, effector versus target ratio was 60:1). Both alphabeta T and gammadelta T cells in the iDCs(Zol)-CIK cells performed the majority of lysis. The iDCs/mDCs(Zol)-CIK cells greatly increased NKG2D expression compared with mDCs-CIK and CIK(Zol) during culture (71.5 +/- 11.3% and 67.7 +/- 9.3% versus 51.3 +/- 6.2% and 47.1 +/- 5.7%). iDCs(Zol)-CIK cell-mediated lysis dropped 69.21% when the NKG2D receptor was blocked and the cytotoxicity correlated with NKG2D ligand-MICA expression on the target cells. In a human myeloma bearing nude mice model, iDCs(Zol)-CIK and mDCs(Zol)-CIK cells treatment groups obtained 75% and 62.5% long-term survival (>120 days) respectively, as compared with none of the control animals or 37.5% treated with mDCs-CIK cells.
CONCLUSION: Large numbers of CIK cells with greater anti-tumor activities are rapidly generated by Zol-treated iDCs/mDCs. This strategy is worthy of further investigation to improve adoptive cell therapy against tumors.

PMID: 20549316 [PubMed - in process]
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Old 06-29-2009, 09:33 PM   #16
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Cancer Res. 2010 Sep 15;70(18):7063-72. Epub 2010 Sep 7.
Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases.

Endo-Munoz L, Cumming A, Rickwood D, Wilson D, Cueva C, Ng C, Strutton G, Cassady AI, Evdokiou A, Sommerville S, Dickinson I, Guminski A, Saunders NA.
The University of Queensland, Level 4, R Wing, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia.


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Abstract

We conducted a transcriptomic screen of osteosarcoma (OS) biopsies and found that expression of osteoclast-specific tartrate-resistant acid phosphatase 5 (ACP5/TRAP) is significantly downregulated in OS compared with nonmalignant bone (P < 0.0001). Moreover, lesions from OS patients with pulmonary metastases had 2-fold less ACP5/TRAP expression (P < 0.018) than lesions from patients without metastases. In addition, we found a direct correlation (P = 0.0166) between ACP5/TRAP expression and time to metastasis. Therefore, we examined whether metastasis-competent (MC) OS cells could induce loss of ACP5(+) osteoclasts and contribute to metastasis. We found that MC OS cell lines can inhibit osteoclastogenesis in vitro and in vivo. In addition, osteoclasts can inhibit the migration of MC OS cells in vitro. Finally, ablation of osteoclasts with zoledronic acid increases the number of metastatic lung lesions in an orthotopic OS model, whereas fulvestrant treatment increases osteoclast numbers and reduces metastatic lesions. These data indicate that the metastatic potential of OS is determined early in tumor development and that loss of osteoclasts in the primary lesion enhances OS metastasis.

PMID: 20823153 [PubMed - in process]
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Old 07-14-2009, 05:08 PM   #17
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Old 07-14-2009, 05:15 PM   #18
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Old 07-18-2009, 12:58 PM   #19
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1: Cancer Lett. 2009 Jul 2. [Epub ahead of print] Links
Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells.

Rachner TD, Singh SK, Schoppet M, Benad P, Bornhäuser M, Ellenrieder V, Ebert R, Jakob F, Hofbauer LC.
Division of Gastroenterology and Endocrinology, Department of Medicine, Philipps-University, Marburg, Germany; Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University, Dresden, Germany.
Breast cancer has a propensity to metastasize to bone, thus causing pathological fractures. Bisphosphonates are established drugs in the treatment of bone metastasis that inhibit osteoclast activity and interrupt the vicious cycle of osteoclast-tumor cell interactions. We evaluated the direct effects of zoledronic acid on estrogen receptor (ER)-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells. While zoledronic acid (100muM) inhibited MDA-MB-231 cell proliferation after 72h, and induced apoptosis via activation of caspase-3 and -7, it had only minor effects on MCF-7 cells. In addition, zoledronic acid induced apoptosis by up-regulating TNF-related apoptosis-inducing ligand (TRAIL) in MDA-MB-231 cells (p<0.01), but had no effect on the expression of its decoy receptor osteoprotegerin (OPG). In MCF-7 cells, both cytokines were suppressed by zoledronic acid. In conclusion, zoledronic acid enhanced the TRAIL-to-OPG ratio in TRAIL-sensitive MDA-MB-231 cells, indicating that the TRAIL/OPG cytokine system is a bisphosphonate-responsive target in breast cancer.
PMID: 19577359 [PubMed - as supplied by publisher]

Hmmmm. So..it showed little response in Er+ cells despite suppresssing more cytokines than when used on ER-????
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Old 08-13-2009, 11:03 AM   #20
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

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